Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KLHL40 : Severe congenital nemaline myopathy

MONDO:0015735 | OMIM:615348
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
13.00
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549); Todd EJ et al. 2015 Nov 17 (PMID:26578207);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
16.25
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549); Kawase K et al. 2015 Oct (PMID:25721947); Todd EJ et al. 2015 Nov 17 (PMID:26578207);
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
2.00
2  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549);
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 1.00
Garg A et al. 2014 Aug (PMID:24960163);
Expression 0.5 0 - 2 1.00
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4.00 4
Ravenscroft G et al. 2013 Jul 11 (PMID:23746549); Garg A et al. 2014 Aug (PMID:24960163);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
10/09/2017
EXPERT CURATION (DATE)
DEFINITIVE
10/11/2017
Approved by J. Berg